CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?

References

• Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19(suppl_5):v1–v88.
   PubMed Web of Science ®Google Scholar
• Ruella M, June CH. Chimeric antigen receptor T cells for B cell neoplasms: choose the right CAR for you. Curr Hematol Malig Rep. 2016;11(5):368–384.
   PubMed Web of Science ®Google Scholar
• Park JH, Geyer MB, Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood. 2016;127(26):3312–3320.
   PubMed Web of Science ®Google Scholar
• Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–2720.
   PubMed Web of Science ®Google Scholar
• Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–549.
   PubMed Web of Science ®Google Scholar
• Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. NEnglJMed. 2014;371(16):1507–1517.
   PubMed Web of Science ®Google Scholar
• Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517–528.
   PubMed Web of Science ®Google Scholar
• Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):355ra116.
   PubMed Web of Science ®Google Scholar
• Turtle CJ, Riddell SR, Maloney DG. CD19-Targeted chimeric antigen receptor-modified T-cell immunotherapy for B-cell malignancies. Clin Pharmacol Ther. 2016;100(3):252–258.
   PubMed Web of Science ®Google Scholar
• Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322–3331.
   PubMed Web of Science ®Google Scholar
• Brentjens RJ, Davila ML, Riviere I, et al. CD19-Targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. SciTranslMed. 2013;5(177):177ra38.
   PubMed Web of Science ®Google Scholar
• Park JH, Riviere I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–459.
   PubMed Web of Science ®Google Scholar
• O’Rourke DM, Nasrallah MP, Desai A, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017; 9(399)
   PubMed Web of Science ®Google Scholar
• Ahmed N, Brawley V, Hegde M, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncology. 2017;3(8):1094–1101.
   PubMed Web of Science ®Google Scholar
• Brown CE, Badie B, Barish ME, et al. Bioactivity and safety of IL13Ralpha2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res. 2015;21(18):4062–4072.
   PubMed Web of Science ®Google Scholar
• Heczey A, Louis CU, Savoldo B, et al. CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Mol Ther. 2017;25(9):2214–2224.
   PubMed Web of Science ®Google Scholar
• Nduom EK, Weller M, Heimberger AB. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 2015;17(Suppl 7):vii9–vii14.
   PubMed Web of Science ®Google Scholar
• Perng P, Lim M. Immunosuppressive mechanisms of malignant gliomas: parallels at non-cns sites. Front Oncol. 2015;5:153.
   PubMed Web of Science ®Google Scholar
• Dotti G, Gottschalk S, Savoldo B, et al. Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev. 2014;257(1):107–126.
   PubMed Web of Science ®Google Scholar
• Jensen MC, Riddell SR. Designing chimeric antigen receptors to effectively and safely target tumors. Curr Opin Immunol. 2015;33:9–15.
   PubMed Web of Science ®Google Scholar
• Sadelain M. Chimeric antigen receptors: driving immunology towards synthetic biology. Curr Opin Immunol. 2016;41:68–76.
   PubMed Web of Science ®Google Scholar
• Urbanska K, Lanitis E, Poussin M, et al. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res. 2012;72(7):1844–1852.
   PubMed Web of Science ®Google Scholar
• Rafiq S, Purdon TJ, Daniyan AF, et al. Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular wilms tumor 1 antigen. Leukemia. 2017;31(8):1788–1797.
   PubMed Web of Science ®Google Scholar
• Kawalekar OU, O’Connor RS, Fraietta JA, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44(2):380–390.
   PubMed Web of Science ®Google Scholar
• Zhao Z, Condomines M, Van Der Stegen SJC, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015;28(4):415–428.
   PubMed Web of Science ®Google Scholar
• Kahlon KS, Brown C, Cooper LJ, et al. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 2004;64(24):9160–9166.
   PubMed Web of Science ®Google Scholar
• Brown CE, Aguilar B, Starr R, et al. Optimization of IL13Ralpha2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. mol ther. 2018;26(1):31–44.
   Web of Science ®Google Scholar
• Ahmed N, Salsman VS, Kew Y, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. ClinCancer Res. 2010;16(2):474–485.
   Google Scholar
• Chow KK, Naik S, Kakarla S, et al. T cells redirected to Epha2 for the immunotherapy of glioblastoma. molther. 2013;21(3):629–637.
   Google Scholar
• Krenciute G, Krebs S, Torres D, et al. Characterization and functional analysis of scFv-based chimeric antigen receptors to redirect t cells to Il13ralpha2-positive glioma. Mol Ther. 2016;24(2):354–363.
   PubMed Web of Science ®Google Scholar
• Krebs S, Chow KK, Yi Z, et al. T cells redirected to interleukin-13Ralpha2 with interleukin-13 mutein-chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Ralpha1. Cytotherapy. 2014;16(8):1121–1131.
   PubMed Web of Science ®Google Scholar
• Caruso HG, Hurton LV, Najjar A, et al. Tuning sensitivity of CAR to egfr density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 2015;75(17):3505–3518.
   PubMed Web of Science ®Google Scholar
• Bullain SS, Sahin A, Szentirmai O, et al. Genetically engineered T cells to target EGFRvIII expressing glioblastoma. J Neurooncol. 2009.
   PubMed Web of Science ®Google Scholar
• Morgan RA, Johnson LA, Davis JL, et al. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. HumGeneTher. 2012;23(10):1043–1053.
   Google Scholar
• Shen CJ, Yang YX, Han EQ, et al. Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma. JHematolOncol. 2013;6:33.
   Google Scholar
• Johnson LA, Scholler J, Ohkuri T, et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015;7(275):275ra22.
   PubMed Web of Science ®Google Scholar
• Shaffer DR, Savoldo B, Yi Z, et al. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood. 2011;117(16):4304–4314.
   PubMed Web of Science ®Google Scholar
• Jin L, Ge H, Long Y, et al. CD70, a novel target of CAR-T-cell therapy for gliomas. Neuro Oncol. 2018;20(1):55–65.
   PubMedGoogle Scholar
• Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. JClinInvest. 2011;121(5):1822–1826.
   PubMed Web of Science ®Google Scholar
• Watanabe N, Bajgain P, Sukumaran S, et al. Fine-tuning the CAR spacer improves T-cell potency. Oncoimmunology. 2016;5(12):e1253656.
   PubMed Web of Science ®Google Scholar
• Hudecek M, Sommermeyer D, Kosasih PL, et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol Res. 2015;3(2):125–135.
   PubMed Web of Science ®Google Scholar
• Casucci M, Nicolis Di Robilant B, Falcone L, et al. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood. 2013;122(20):3461–3472.
   PubMed Web of Science ®Google Scholar
• Jonnalagadda M, Mardiros A, Urak R, et al. Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther. 2015;23(4):757–768.
   PubMed Web of Science ®Google Scholar
• Bridgeman JS, Hawkins RE, Bagley S, et al. The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. JImmunol. 2010;184(12):6938–6949.
   PubMed Web of Science ®Google Scholar
• Gomes-Silva D, Mukherjee M, Srinivasan M, et al. tonic 4-1bb costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. cell Rep. 2017;21(1):17–26.
   PubMed Web of Science ®Google Scholar
• Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–117.
   PubMed Web of Science ®Google Scholar
• Sabatino M, Hu J, Sommariva M, et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood. 2016;128(4):519–528.
   PubMed Web of Science ®Google Scholar
• Held-Feindt J, Mentlein R. CD70/CD27 ligand, a member of the TNF family, is expressed in human brain tumors. IntJCancer. 2002;98(3):352–356.
   Google Scholar
• Wischhusen J, Jung G, Radovanovic I, et al. Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. Cancer Res. 2002;62(9):2592–2599.
   PubMed Web of Science ®Google Scholar
• Aulwurm S, Wischhusen J, Friese M, et al. Immune stimulatory effects of CD70 override CD70-mediated immune cell apoptosis in rodent glioma models and confer long-lasting antiglioma immunity in vivo. Int J Cancer. 2006;118(7):1728–1735.
   PubMed Web of Science ®Google Scholar
• Pratt D, Pittaluga S, Palisoc M, et al. Expression of CD70 (CD27L) is associated with epithelioid and sarcomatous features in IDH-wild-type glioblastoma. J Neuropathol Exp Neurol. 2017;76(8):697–708.
   PubMed Web of Science ®Google Scholar
• Ge H, Mu L, Jin L, et al. Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM. Int J Cancer. 2017;141(7):1434–1444.
   PubMed Web of Science ®Google Scholar
• Zadeh G, Bhat KP, Aldape K. EGFR and EGFRvIII in glioblastoma: partners in crime. Cancer Cell. 2013;24(4):403–404.
   PubMed Web of Science ®Google Scholar
• Padfield E, Ellis HP, Kurian KM. Current therapeutic advances targeting EGFR and EGFRvIII in glioblastoma. Front Oncol. 2015;5:5.
   PubMed Web of Science ®Google Scholar
• Montano N, Cenci T, Martini M, et al. Expression of EGFRvIII in glioblastoma: prognostic significance revisited. Neoplasia. 2011;13(12):1113–1121.
   PubMed Web of Science ®Google Scholar
• Felsberg J, Hentschel B, Kaulich K, et al. Epidermal growth factor receptor variant iii (EGFRviii) positivity in EGFR-amplified glioblastomas: prognostic role and comparison between primary and recurrent tumors. clin cancer res. 2017.
   PubMed Web of Science ®Google Scholar
• Wykosky J, Gibo DM, Stanton C, et al. EphA2 as a novel molecular marker and target in glioblastoma multiforme. MolCancer Res. 2005;3(10):541–551.
   Web of Science ®Google Scholar
• Wykosky J, Gibo DM, Stanton C, et al. Interleukin-13 receptor alpha 2, EphA2, and Fos-related antigen 1 as molecular denominators of high-grade astrocytomas and specific targets for combinatorial therapy. ClinCancer Res. 2008;14(1):199–208.
   Google Scholar
• Hernan R, Fasheh R, Calabrese C, et al. ERBB2 up-regulates S100A4 and several other prometastatic genes in medulloblastoma. Cancer Res. 2003;63(1):140–148.
   PubMed Web of Science ®Google Scholar
• Koka V, Potti A, Forseen SE, et al. Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme. AmJClinOncol. 2003;26(4):332–335.
   Google Scholar
• Liu G, Ying H, Zeng G, et al. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res. 2004;64(14):4980–4986.
   PubMed Web of Science ®Google Scholar
• Zhang JG, Kruse CA, Driggers L, et al. Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy. JNeurooncol. 2008;88(1):65–76.
   PubMed Web of Science ®Google Scholar
• Debinski W, Obiri NI, Powers SK, et al. Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. ClinCancer Res. 1995;1(11):1253–1258.
   Google Scholar
• Saikali S, Avril T, Collet B, et al. Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Ralpha2, gp100 and TRP-2 for immunotherapy. J Neurooncol. 2007;81(2):139–148.
   PubMed Web of Science ®Google Scholar
• Kawakami M, Kawakami K, Takahashi S, et al. Analysis of interleukin-13 receptor alpha2 expression in human pediatric brain tumors. Cancer. 2004;101(5):1036–1042.
   PubMed Web of Science ®Google Scholar
• Okada H, Low KL, Kohanbash G, et al. Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas. J Neurooncol. 2008;88(3):245–250.
   PubMed Web of Science ®Google Scholar
• Joshi BH, Puri RA, Leland P, et al. Identification of interleukin-13 receptor alpha2 chain overexpression in situ in high-grade diffusely infiltrative pediatric brainstem glioma. NeuroOncol. 2008;10(3):265–274.
   Google Scholar
• Lanitis E, Poussin M, Klattenhoff AW, et al. Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol Res. 2013;1(1):43–53.
   PubMed Web of Science ®Google Scholar
• Brown CE, Starr R, Aguilar B, et al. Stem-like tumor-initiating cells isolated from IL13Ralpha2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T cells. Clin Cancer Res. 2012;18(8):2199–2209.
   PubMed Web of Science ®Google Scholar
• Coffman KT, Hu M, Carles-Kinch K, et al. Differential EphA2 epitope display on normal versus malignant cells. Cancer Res. 2003;63(22):7907–7912.
   PubMed Web of Science ®Google Scholar
• Damschroder MM, Widjaja L, Gill PS, et al. Framework shuffling of antibodies to reduce immunogenicity and manipulate functional and biophysical properties. MolImmunol. 2007;44(11):3049–3060.
   Google Scholar
• Krenciute G, Prinzing BL, Yi Z, et al. Transgenic expression of IL15 improves antiglioma activity of IL13ralpha2-CAR T cells but results in antigen loss variants. Cancer Immunol Res. 2017;5(7):571–581.
   PubMed Web of Science ®Google Scholar
• Hegde M, Corder A, Chow KK, et al. Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. Mol Ther. 2013;21(11):2087–2101.
   PubMed Web of Science ®Google Scholar
• Hegde M, Mukherjee M, Grada Z, et al. Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape. J Clin Invest. 2016;126(8):3036–3052.
   PubMed Web of Science ®Google Scholar
• Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest. 2016;126(10):3814–3826.
   PubMed Web of Science ®Google Scholar
• Bielamowicz K, Fousek K, Byrd TT, et al. Trivalent CAR T-cells overcome interpatient antigenic variability in glioblastoma. Neuro Oncol. 2017.
   PubMedGoogle Scholar
• Sampson JH, Choi BD, Sanchez-Perez L, et al. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res. 2014;20(4):972–984.
   PubMed Web of Science ®Google Scholar
• Wang X, Chang WC, Wong CW, et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood. 2011;118(5):1255–1263.
   PubMed Web of Science ®Google Scholar
• Keu KV, Witney TH, Yaghoubi S, et al. Reporter gene imaging of targeted T cell immunotherapy in recurrent glioma. Sci Transl Med. 2017;9:373.
   Web of Science ®Google Scholar
• Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. n engl j med. 2016;375(26):2561–2569.
   PubMed Web of Science ®Google Scholar
• Lucas KG, Bao L, Bruggeman R, et al. The detection of CMV pp65 and IE1 in glioblastoma multiforme. J Neurooncol. 2011;103(2):231–238.
   PubMedGoogle Scholar
• Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–1034.
   PubMed Web of Science ®Google Scholar
• Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.
   PubMed Web of Science ®Google Scholar
• Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94(1):25–39.
   PubMed Web of Science ®Google Scholar
• Zhu VF, Yang J, Lebrun DG, et al. Understanding the role of cytokines in glioblastoma multiforme pathogenesis. cancer lett. 2012;316(2):139–150.
   PubMed Web of Science ®Google Scholar
• Kesarwani P, Kant S, Prabhu A, et al. The interplay between metabolic remodeling and immune regulation in glioblastoma. Neuro Oncol. 2017;19(10):1308–1315.
   PubMed Web of Science ®Google Scholar
• Hurton LV, Singh H, Najjar AM, et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci U S A. 2016;113(48):E7788–E7797.
   PubMed Web of Science ®Google Scholar
• Hoyos V, Savoldo B, Quintarelli C, et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia. 2010;24(6):1160–1170.
   PubMed Web of Science ®Google Scholar
• Koneru M, Purdon TJ, Spriggs D, et al. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology. 2015;4(3):e994446.
   PubMed Web of Science ®Google Scholar
• Yeku OO, Purdon TJ, Koneru M, et al. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci Rep. 2017;7(1):10541.
   PubMedGoogle Scholar
• Chmielewski M, Kopecky C, Hombach AA, et al. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res. 2011;71(17):5697–5706.
   PubMed Web of Science ®Google Scholar
• Hu B, Ren J, Luo Y, et al. augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. cell rep. 2017;20(13):3025–3033.
   PubMed Web of Science ®Google Scholar
• Zhang L, Morgan RA, Beane JD, et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res. 2015;21(10):2278–2288.
   PubMed Web of Science ®Google Scholar
• Hunter MR, Prosser ME, Mahadev V, et al. Chimeric gammac cytokine receptors confer cytokine independent engraftment of human T lymphocytes. Mol Immunol. 2013;56(1–2):1–11.
   PubMed Web of Science ®Google Scholar
• Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481(7380):157–163.
   PubMed Web of Science ®Google Scholar
• Shum T, Omer B, Tashiro H, et al. Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discov. 2017;7(11):1238–1247.
   PubMed Web of Science ®Google Scholar
• Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8(5):369–380.
   PubMed Web of Science ®Google Scholar
• Bollard CM, Rossig C, Calonge MJ, et al. Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. Blood. 2002;99(9):3179–3187.
   PubMed Web of Science ®Google Scholar
• Bollard CM, Gottschalk S, Torrano V, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. JClinOncol. 2014;32(8):798–808.
   Google Scholar
• Wilkie S, Burbridge SE, Chiapero-Stanke L, et al. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. JBiolChem. 2010;285(33):25538–25544.
   PubMed Web of Science ®Google Scholar
• Leen AM, Sukumaran S, Watanabe N, et al. Reversal of tumor immune inhibition using a chimeric cytokine receptor. MolTher. 2014;22(6):1211–1220.
   Google Scholar
• Watanabe N, Anurathapan U, Brenner M, et al. Transgenic expression of a novel immunosuppressive signal converter on T cells. MolTher. 2013;22(S1):S153.
   Google Scholar
• Berghoff AS, Kiesel B, Widhalm G, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 2015;17(8):1064–1075.
   PubMed Web of Science ®Google Scholar
• Nduom EK, Wei J, Yaghi NK, et al. PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol. 2016;18(2):195–205.
   PubMed Web of Science ®Google Scholar
• Zeng J, Zhang XK, Chen HD, et al. Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas. Oncotarget. 2016;7(8):8944–8955.
   PubMedGoogle Scholar
• Wainwright DA, Chang AL, Dey M, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res. 2014;20(20):5290–5301.
   PubMed Web of Science ®Google Scholar
• Reardon DA, Omuro A, Brandes AA, et al. OS10.3 randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: checkMate 143. Neuro Oncol. 2017;19(suppl_3):iii21–iii.
   Google Scholar
• Bouffet E, Larouche V, Campbell BB, et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol. 2016;34(19):2206–2211.
   PubMed Web of Science ®Google Scholar
• Rupp LJ, Schumann K, Roybal KT, et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep. 2017;7(1):737.
   PubMed Web of Science ®Google Scholar
• Li S, Siriwon N, Zhang X, et al. Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors. Clin Cancer Res. 2017;23(22):6982–6992.
   PubMed Web of Science ®Google Scholar
• Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126(8):3130–3144.
   PubMed Web of Science ®Google Scholar
• Ankri C, Shamalov K, Horovitz-Fried M, et al. Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J Immunol. 2013;191(8):4121–4129.
   PubMed Web of Science ®Google Scholar
• Liu X, Ranganathan R, Jiang S, et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 2016;76(6):1578–1590.
   PubMed Web of Science ®Google Scholar
• Pellegatta S, Savoldo B, Di Ianni N, et al. Constitutive and TNFalpha-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: implications for CAR-T cell therapy. Sci Transl Med. 2018;10:430.
   Web of Science ®Google Scholar
• Johanns TM, Dunn GP. Applied cancer immunogenomics: leveraging neoantigen discovery in glioblastoma. Cancer J. 2017;23(2):125–130.
   PubMed Web of Science ®Google Scholar
• Butterfield LH, Ribas A, Dissette VB, et al. Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. ClinCancer Res. 2003;9(3):998–1008.
   Google Scholar
• Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. NEnglJMed. 2008;358(25):2698–2703.
   PubMed Web of Science ®Google Scholar
• Kakarla S, Wang L, Rowley D, et al. Improving T-cell immunotherapies for solid tumors by targeting the tumor stroma. Biol Blood Marrow Transplant. 2011;17(2(supplement 1)):S270.
   PubMed Web of Science ®Google Scholar
• Bentley RT, Ahmed AU, Yanke AB, et al. Dogs are man’s best friend: in sickness and in health. Neuro Oncol. 2017;19(3):312–322.
   PubMed Web of Science ®Google Scholar
• Di Stasi A, De Angelis B, Rooney CM, et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood. 2009;113(25):6392–6402.
   PubMed Web of Science ®Google Scholar
• Craddock JA, Lu A, Bear A, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunotherapy. 2010;33(8):780–788.
   PubMed Web of Science ®Google Scholar
• Caruana I, Savoldo B, Hoyos V, et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015;21(5):524–529.
   PubMed Web of Science ®Google Scholar
• Berger C, Flowers ME, Warren EH, et al. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood. 2006;107(6):2294–2302.
   PubMed Web of Science ®Google Scholar
• Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 2015;16(15):e534–42.
   PubMedGoogle Scholar
• Westphal M, Lamszus K. Circulating biomarkers for gliomas. Nat Reviews Neurol. 2015;11(10):556–566.
   PubMed Web of Science ®Google Scholar
• Schuessler A, Smith C, Beagley L, et al. Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res. 2014;74(13):3466–3476.
   PubMed Web of Science ®Google Scholar
• Chheda ZS, Kohanbash G, Okada K, et al. Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. J Exp Med. 2018;215(1):141–157.
   PubMed Web of Science ®Google Scholar
• Suck G, Odendahl M, Nowakowska P, et al. NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother. 2016;65(4):485–492.
   PubMed Web of Science ®Google Scholar
• Heczey A, Liu D, Tian G, et al. Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood. 2014.
   PubMed Web of Science ®Google Scholar
• Zhang C, Burger MC, Jennewein L, et al. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. JNCI: J Natl Cancer Inst. 2016;108(5).
   Web of Science ®Google Scholar
• Baker GJ, Chockley P, Yadav VN, et al. Natural killer cells eradicate galectin-1-deficient glioma in the absence of adaptive immunity. Cancer Res. 2014;74(18):5079–5090.
   PubMed Web of Science ®Google Scholar
• Pereboeva L, Harkins L, Wong S, et al. The safety of allogeneic innate lymphocyte therapy for glioma patients with prior cranial irradiation. Cancer Immunol Immunother. 2015;64(5):551–562.
   PubMed Web of Science ®Google Scholar
• Iwami K, Shimato S, Ohno M, et al. Peptide-pulsed dendritic cell vaccination targeting interleukin-13 receptor alpha2 chain in recurrent malignant glioma patients with HLA-A*24/A*02 allele. Cytotherapy. 2012;14(6):733–742.
   PubMed Web of Science ®Google Scholar
• Okada H, Kalinski P, Ueda R, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. JClinOncol. 2011;29(3):330–336.
   Google Scholar